Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants-rs6913677 in BAI3 gene (p = 1.08 × 10-8) and rs2078267 in SLC22A11 gene (p = 4.62 × 10-8) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10-7) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10-7), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.

中文翻译：

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多方面的全基因组研究确定了SLC22A11和ZNF45中印度人体重指数的新调控位点。

肥胖是多种疾病（例如糖尿病，高血压，癌症）的危险因素，其起源是基因与流行环境（饮食习惯和生活方式）之间复杂的相互作用，而这种相互作用因人群而异。与匹配的白人人群相比，印度人在给定的体重下表现出独特的肥胖表型，腹部肥胖率高，这表明存在影响肥胖的特定人群遗传和环境因素。但是，尚未探索印度肥胖的特定人群遗传因素。因此，为了确定潜在的遗传贡献者，我们进行了两阶段的全基因组关联研究（GWAS），以评估体重指数（BMI），这是评估5973名印度成年人肥胖的常见措施，并且在1286名印度人中进一步重复了主要发现青少年。我们的研究揭示了在GWAS意义上，BAI3基因（p = 1.08×10-8）和SLC22A11基因（p = 4.62×10-8）的rs2078267和ZNF45基因（p = 1.04× 10-7）具有接近GWAS的意义。由于遗传位点可能通过表观遗传过程的调控决定了表型，因此我们在236名印度人中将已识别信号的遗传数据与其DNA甲基化模式进行了重叠，并进行了甲基化定量特征位点（meth-QTL）分析。此外，使用公开可用的基因调节数据库（ENCODE，JASPAR，GeneHancer，GTEx）推测发现的变体和基础基因的功能作用。发现在BAI3和SLC22A11基因中鉴定出的变异体决定了在具有关键的顺式调控元件的独特CpG处的甲基化模式。此外，BAI3 SLC22A11和ZNF45变体分别位于ENCODE数据库中人皮下脂肪组织中的阻抑染色质，活性增强剂和活性染色质区域中。另外，这些基因组区域代表与肥胖和/或代谢异常有关的关键转录因子的潜在结合位点。有趣的是，GTEx门户网站将rs8100011确定为皮下脂肪组织中的稳健的顺式表达数量性状基因座（p = 1.6×10-7），并且印度受试者骨骼肌中ZNF45基因表达与BMI呈负相关。说明其在肥胖症中的可能作用。总之，我们的研究在印度人的BMI中发现了2个新的（SLC22A11和ZNF45）和1个较早报道的BMI基因（BAI3），这3个新的特定于人群的功能性遗传变异（rs6913677，rs2078267，rs8100011）。